Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2a, A2b, and A3, all of which modulate important physiological processes. For example, stimulation of the A1 adenosine receptors shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. A2A adenosine receptors modulate coronary vasodilation, A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148–153). A3 adenosine receptors modulate cell proliferation processes. In particular, compounds that are A3 receptor agonists have utility in the therapeutic and/or prophylactic treatment of cancer, cardiac disease, infertility, kidney disease, and CNS disorders. Additionally, A3 receptor agonists stimulate bone marrow cell proliferation, and thus induce the secretion of G-CSF in the body. Accordingly, A3 receptor agonists are useful for countering the toxic side effect of drugs, in particular chemotherapeutic drugs, such as leukopenia and neutropenia.
Few ligands for the A3 adenosine receptor have been reported. Some non-selective N6-substituted adenosine derivatives have been described as agonists for the A3 receptor, including APNEA (N6-2-(4-aminophenyl)ethyladenosine), which has been used successfully as a radioligand in its iodinated form (Zhou et al.). Typical xanthine and nonxanthine A1 and A2 receptor antagonists, however, do not appear to bind to this receptor (Zhou et al.).
Accordingly, it is desired to provide compounds that are A3 receptor agonists. Preferably, the compounds would be selective for the A3 receptor, thus avoiding side effects caused by interaction with other adenosine receptors.